Exercise or physical activity has long been reported to play a major role in the control of body weight. A number of clinical studies have shown that whereas physical inactivity contributes to the development of obesity, exercise improves weight loss and, added to dietary control, becomes a key factor for success in long- term weight maintenance in overweight and obese patients. Recent work with rodent obesity models has shown that exercise affects energy balance not only by increasing energy expenditure, but also by altering appetite and reducing food intake. Despite these demonstrated effects of exercise, how exercise affects food intake and body weight remains poor understood. The long-term goal of this project is to identify the neural mechanisms underlying the effects of exercise on energy balance. The hypothalamus plays a central role in maintaining energy homeostasis. To identify hypothalamic factors that mediate exercise-induced alterations in food intake and body weight, we have examined hypothalamic gene expression in response to running wheel activity using microarray analyses. These analyses have shown that transthyretin (TTR) gene expression is induced in the dorsomedial hypothalamus (DMH) of exercised rats. We have also shown that central injection of TTR inhibits food intake. Based on these data and the prior observation that TTR knockout results in increased neuropeptide Y levels in mouse peripheral and central nerve systems, we hypothesize that brain TTR may be a major contributing factor to the effects of exercise on food intake and energy balance, and together with other peptides, plays an important role in energy homeostasis. We propose two specific aims to test this hypothesis. Specific Aim 1 will identify the role of brain TTR in the control of energy balance using multiple approaches at neurochemical, pharmacological, genetic and protein levels. Specific Aim 2 will ascertain the target sites and mechanisms of actions of brain TTR in the control of energy balance by gene expression determination and proteomic analysis. Overall, the findings from this proposal will not only advances our understanding of the neurobiological impact of exercise on energy balance, but also provide a potential target for combating obesity. PUBLIC HEALTH RELEVANCE: This proposed project is aimed at identifying the neural mechanisms underlying the effects of exercise on energy balance. Such identification will provide a potential target for the prevention and treatment of obesity.